TAK1 kinase is an essential signaling intermediate involving multiple signaling pathways including TNF, IL-1, and stress pathways. We have recently demonstrated that the targeted deletion of TAK1 in multiple epithelial tissues causes cell death and inflammatory conditions. Thus, TAK1 is critically involved in tissue homeostasis by regulating cell death. Although TAK1 regulation of pro-inflammatory signaling leading to cytokine production has been well studied, the TAK1 pathways regulating cell death remain elusive. We have identified that TAK1 regulates the level of reactive oxygen species (ROS). TAK1 binding proteins, TAB1 and TAB2, differentially participate in TAK1 signaling; TAB2 mediates cytokine-induced TAK1 activation, whereas TAB1 mediates activation of TAK1 specifically in response to stress. We hypothesize that TAK1 regulates cell survival and inflammation in vivo by modulating ROS, and that TAB1 and TAB2 regulate TAK1-cell survival signaling in response to stimulus unique to each protein. The long-term objective is to delineate the TAK1 signaling network regulating tissue homeostasis. In short- term, we aim to determine the roles of TAK1, TAB1 and TAB2 in ROS-dependent cell death pathway. Outcomes from this project will enhance our understanding of tissue homeostasis specifically regulation of ROS, cell death and inflammation, which could lead to new approaches to improve many inflammatory conditions that are associated with ROS. PUBLIC HEALTH RELEVANCE: To maintain tissue integrity, cells need to prevent unscheduled cell death, which could induce tissue damages and inflammation. In many tissues, potential cell death inducers such as cytokines and stressors constantly present even in normal conditions; however cells are resistant to those inducers. We have found that mice having deletion of TAK1 kinase in the epithelial tissues spontaneously develop tissue damages associated with cell death. This suggests that TAK1 kinase activity is important to prevent cell death in normal tissues. In this project, we will determine the mechanism by which TAK1 controls cell death and define how TAK1 kinase activity is regulated in normal tissues. The outcomes enhance our understanding of the regulatory mechanism of tissue integrity, which could lead new approaches to prevent tissue damage-associated pathogenic conditions.